of individuals, groups,communities and populations;women as research subjects;equityregarding burdens and benefits;choice of control in clinical trials;confidentiality; compensation forinjury; strengthening of national orlocal capacity for ethical review; andobligations of sponsors to providehealth-care services.

Their scope reflects thechanges, the advances and thecontroversies that havecharacterized biomedical researchethics in the last two decades. Likethose of 1982 and 1993, the 2002CIOMS Guidelines are designed tobe of use to countries in definingnational policies on the ethics ofbiomedical research involvinghuman subjects, applying ethicalstandards in local circumstances,and establishing or improvingethical review mechanisms. Aparticular aim is to reflect theconditions and the needs of low-resource countries, and theimplications for multinational ortransnational research in which theymay be partners.

ethical guidelines issued by CIOMSsince 1982. Its core consists of 21guidelines with commentaries. Aprefatory section outlines thehistorical background and therevision process, and includes

anintroduction, an account of earlierinstruments and guidelines, astatement of ethical principles and apreamble. An Appendix lists theitems to be included in the researchprotocol to be submitted forscientific and ethical review andclearance. Appendices include alsothe World Medical Association'sDeclaration of Helsinki.

Prepared by the Council for International Organizations of MedicalSciences (CIOMS) in collaboration with the World Health Organization(WHO)

CIOMS

Geneva

2002

CONTENTS

ACKNOWLEDGEMENTS

BACKGROUND

INTRODUCTION

INTERNATIONAL INSTRUMENTS AND GUIDELINES

GENERAL ETHICAL PRINCIPLES

PREAMBLE

THE GUIDELINES

Ethical justification and scientific validity

of

biomedical research involving humansubjects

Ethical review

Ethical review committees

Ethical review of externally sponsoredresearch

Informed consent

Individual informed consent

Obtaining informed consent: Essential

information for prospective researchsubjects

Obtaining informed consent: Obligationsof sponsors and investigators

Inducement to participate

Benefits and risks of study participation

Special limitations on risk whenresearch involves

individuals who arenot capable of giving informed consent

* * * * *

Research in populations and communitieswith limited resources

* * * * *

Choice of control in clinical trials

Vulnerable groups

Equitable distribution of burdens andbenefits in the selection of groups ofsubjects in research

Research involving vulnerable persons

Research involving children

Research involving individuals who byreason of mental or behaviouraldisorders are not capable of givingadequately informed consent

Women as research participants

Women as research participants

Pregnant women as researchparticipants

* * * * *

Safeguarding confidentiality

Right of injured subjects to treatmentand compensation

Strengthening capacity for ethical andscientific review

and biomedicalresearch

Ethical obligation

of external sponsors toprovide health-care services

Appendix 1: Items to be included in a protocol (or associated documents)

forbiomedical research involving human subjects.

Appendix 2: The Declaration of Helsinki

Appendix 3: The phases of clinicaltrials of vaccines and drugs

ACKNOWLEDGEMENTS

The Council for International Organizations of Medical Sciences (CIOMS)acknowledges the substantial financial contribution of the Joint United NationsProgramme on HIV/AIDS (UNAIDS) to the preparation of the 2002InternationalEthical Guidelines for

Biomedical Research Involving Human Subjects. TheWorld Health Organization in Geneva contributed generously also through thedepartments of Reproductive Health and Research, Essential Drugs andMedicines Policy, Vaccines and Biologicals, and HIV/AIDS/Sexually TransmittedInfections, as well as the Special Programme for Research and Training inTropical Diseases. CIOMS was at all times free to avail of the services andfacilities of WHO.

CIOMS acknowledges also with much appreciation the financial support to theproject from the Government of Finland, the Government of Switzerland, theSwiss Academy of Medical Sciences,

the Fogarty International Center at theNational Institutes of Health, USA, and the Medical Research Council of theUnited Kingdom.

A number of institutions and organizations made valuable contributions bymaking their experts available at no cost to CIOMS for the three meetings held inrelation to the revision project. This has been highly appreciated.

The task of finalizing the various drafts was in the hands of Professor Robert J.Levine, who served as consultant to the project and chair of the steeringcommittee, and whose profound knowledge and understanding of the field isremarkable. He was ably assisted by Dr James Gallagher of the CIOMSsecretariat, who managed the electronic discussion and endeavoured toaccommodate or reflect in the text the numerous comments received. He alsoedited the final text. Special mention must be made of the informal drafting groupset up to bring the influence of various cultures to bear on the process. Thegroup, with two members of the CIOMS secretariat, met for five days in NewYork in January 2001 and continued for several months to interact electronicallywith one another and with the secretariat to prepare the third draft, posted on theCIOMS website in June 2001: Fernando Lolas Stepke (chair), John Bryant,Leonardo de Castro, Robert Levine, Ruth Macklin, and Godfrey Tangwa; thegroup continued from October 2001, together with Florencia Luna and RodolfoSaracci, to cooperate in preparing the fourth draft. The contribution of this groupwas invaluable.

The interest and comments of the many organizations and individuals whoresponded to the several drafts of the

guidelines posted on the CIOMS websiteor otherwise made available are gratefully acknowledged (Appendix 6)

At CIOMS, Sev Fluss was at all times ready and resourceful when consulted,with advice and constructive comment, and Mrs Kathryn Chalaby-Amslerresponded most competently to the sometimes considerable demands made onher administrative and secretarial skills.

BACKGROUND

The Council for International Organizations of Medical Sciences (CIOMS) is aninternational nongovernmental organization in official relations with the WorldHealth Organization (WHO). It was founded under the auspices of WHO and theUnited Nations Educational, Scientific and Cultural and Organization (UNESCO)in 1949 with among its mandates that of maintaining collaborative relations withthe United Nations and its specialized agencies, particularly with UNESCO andWHO.

CIOMS, in association with WHO, undertook its work on ethics in relation tobiomedical research in the late 1970s. At that time, newly independent WHOMember States were setting up health-care systems. WHO was not then in aposition to promote ethics as an aspect of health care or research. It was thusthat CIOMS set out, in cooperation with WHO, to prepare guidelines " to indicatehow the ethical principles that should guide the conduct of biomedical researchinvolving human subjects, as set forth in the Declaration of Helsinki, could beeffectively applied, particularly in developing countries, given their socioeconomiccircumstances, laws and regulations, and executive and administrativearrangements". The World Medical Association had issued the originalDeclaration of Helsinki in 1964 and an amended version in 1975. The outcome ofthe CIOMS/WHO undertaking was, in 1982,Proposed International EthicalGuidelines for

Biomedical Research Involving Human Subjects.

The period that followed saw the outbreak of the HIV/AIDS pandemic andproposals to undertake large-scale trials of vaccine and treatment drugs for thecondition. These raised new ethical issues that had not been considered in thepreparation ofProposed Guidelines. There were other factors also–

rapidadvances in medicine and biotechnology, changing research practices such asmultinational field trials, experimentation involving vulnerable population groups,and also a changing view, in rich and poor countries, that research involvinghuman subjects was largely beneficial and not threatening.

The Declaration ofHelsinki was revised twice in the 1980s–

in 1983 and 1989. It was timely torevise and update the 1982 guidelines, and CIOMS, with the cooperation ofWHO and its Global Programme on AIDS, undertook the task. The

outcome wasthe issuing of two sets of guidelines: in 1991,International Guidelines for EthicalReview of Epidemiological Studies; and, in 1993,International Ethical Guidelinesfor

Biomedical Research Involving Human Subjects.

After 1993, ethical issues arose for which the CIOMS Guidelines had no specificprovision. They related mainly to controlled clinical trials, with external sponsorsand investigators, carried out in low-resource countries and to the use ofcomparators other than an established effective intervention. The issue inquestion was the perceived need in those countries for low-cost, technologicallyappropriate, public-health solutions, and in particular for HIV/AIDS treatmentdrugs or vaccines that poorer countries could afford. Commentators tookopposing sides on this issue. One advocated, for low-resource countries, trials ofinterventions that, while they might be less effective than the treatment availablein the better-off countries, would be less expensive. All research efforts for publicsolutions appropriate to developing countries should not be rejected as unethical,they claimed. The research context should be considered.

Local decision-makingshould be the norm. Paternalism on the part of the richer countries towardspoorer countries should be avoided. The challenge was to encourage researchfor local solutions to the burden of disease in much of the world, while providingclear guidance on protecting against exploitation of vulnerable communities andindividuals.

The other side argued that such trials constituted, or risked constituting,exploitation of poor countries by rich countries and were inherently unethical.Economic factors should not influence ethical considerations. It was within thecapacity of rich countries or the pharmaceutical industry to make establishedeffective treatment available for comparator purposes. Certain low-resourcecountries had already madeavailable from their own resources establishedeffective treatment for their HIV/AIDS patients.

This conflict complicated the revision and updating of the 1993 Guidelines.Ultimately, it became clear that the conflicting views could not be reconciled,though the proponents of the former view claimed that the new guidelines hadbuilt in effective safeguards against exploitation. The commentary to theGuideline concerned (11) recognizes the unresolved, or unresolvable, conflict.

The revision/updating of the 1993 Guidelines began in December 1998, and afirst draft prepared by the CIOMS consultant for the project was reviewed by theproject steering committee, which met in May 1999. The committee proposedamendments and listed topics on which new or revised guidelines wereindicated; it recommended papers to be commissioned on the topics, as well asauthors and commentators, for presentation and discussion at a CIOMS interimconsultation. It was considered that an interim consultation meeting, of membersof thesteering committee together with the authors of commissioned papers anddesignated commentators, followed by further redrafting and electronicdistribution and feedback, would better serve the purpose of the project than theprocess originally envisaged, which had been to complete the revision in onefurther step. The consultation was accordingly organized for March 2000, inGeneva.

At the consultation, progress on the revision was reported and contentiousmatters reviewed. Eight commissioned papers previously distributed werepresented, commented upon, and discussed.

The work of the consultationcontinued with ad hoc electronic working groups over the following severalweeks, and the outcome was made available for the preparation of the third draft.The material commissioned for the consultation was made the subject of aCIOMS publication:Biomedical Research Ethics: Updating InternationalGuidelines. A Consultation

(December 2000).

An informal redrafting group of eight, from Africa, Asia, Latin America, the UnitedStates and the CIOMS secretariat met in New York City in January 2001, andsubsequently interacted electronically with one another and with the CIOMSsecretariat. A revised draft was posted on the CIOMS website in June 2001 andotherwise widely distributed. Many organizations and individuals commented,some extensively, some critically. Views on certain positions, notably on placebo-controlled trials, were contradictory. For the subsequent revision two memberswere added to the redrafting group, from Europe and Latin America. Theconsequent draft was posted on the website in January 2002 in preparation forthe CIOMS Conference in February/ March 2002

The CIOMS Conference was convened to discuss and, as far as possible,endorse a final draft to be submitted for final approval to the CIOMS ExecutiveCommittee. Besides representation of member organizations of CIOMS,participants included experts in ethics and research from all continents. Theyreviewed the draft guidelines seriatim and suggested modifications. Guideline 11,Choice of control in clinical trials, was redrafted

at

the conference in an effort toreduce disagreement. The redrafted text of that guideline was intensivelydiscussed and generally well received. Some participants, however, continued toquestion the ethical acceptability of the exception to the general rule limiting theuse of placebo to the conditions set out in the guideline; they argued thatresearch subjects should not be exposed to risk of serious or irreversible harmwhen anestablished effective intervention could prevent such harm, and thatsuch exposure could constitute exploitation. Ultimately, the commentary ofGuideline 11 reflects the opposing positions on use of a comparator other thanan established effective intervention for control purposes.

The new text, the 2002 text, which supersedes that of 1993, consists of astatement of general ethical principles, a preamble and 21 guidelines, with anintroduction and a brief account of earlier declarations and guidelines. Like the1982 and 1993 Guidelines, the present publication is designed to be of use,particularly to low-resource countries, in defining national policies on the ethics ofbiomedical research, applying ethical standards in local circumstances, andestablishing or redefining adequate mechanisms for ethical review of researchinvolving human subjects

Comments on the Guidelines are welcome and should be addressed to theSecretary-General, Council for International Organizations of Medical Sciences,c/o World Health Organization, CH-1211 Geneva 27, Switzerland; or by e-mail tocioms@who.int

INTRODUCTION

This is the third in the series of international ethical guidelines for biomedicalresearch involving human subjects issued by the Council for InternationalOrganizations of Medical Sciences since 1982. Its scope and preparation reflectwell the transformation that has occurred in the field of research ethics in thealmost quarter century since CIOMS first undertook to make this contribution tomedical sciences and the ethics of research. The CIOMS Guidelines, with theirstated concern for the application of the Declaration of Helsinki in developingcountries, necessarily reflect the conditions and the needs of biomedicalresearch in those countries, and the implications for multinational or transnationalresearch in which they may be partners.

An issue, mainly for those countries and perhaps less pertinent now than in thepast, has been the extent to which ethical principles are considered universal oras culturally relative–

the universalist versus the pluralist view. The challenge tointernational research ethics is to apply universal ethical principles to biomedicalresearch in a multicultural world with a multiplicity of health-care systems andconsiderable variation in standards of health care.

The Guidelines take theposition that research involving human subjects must not violate any universallyapplicable ethical standards, but acknowledge that, in superficial aspects, theapplication of the ethical principles, e.g., in relation to individual autonomy andinformed consent, needs to take account of cultural values, while respectingabsolutely the ethical standards.

Related to this issue is that of the human rights of research subjects, as well asof health professionals as researchers in a variety of sociocultural contexts, andthe contribution that international human rights instruments can make in theapplication of the general principles of ethics to research involving humansubjects. The issue concerns largely, though not exclusively, two principles:respect for autonomy and protection of dependent or vulnerable persons andpopulations. In the preparation of the Guidelines the potential contribution inthese respects of human rights instruments and norms was discussed, and theGuideline drafters have represented the views of commentators

on safeguardingthe corresponding rights of subjects.

Certain areas

of research are not represented by specific guidelines. One such ishuman genetics. It is, however, considered in Guideline 18 Commentary underIssues of confidentiality in genetics research.

The ethics of genetics researchwas the subject of a commissioned paper and commentary.

Another unrepresented area is research with products of conception (embryo andfetal research, and fetal tissue research). An attempt to craft a guideline on thetopic proved unfeasible. At issue was the moral status of embryos and fetusesand the degree to which risks to the life or well-being of these entities areethically permissible.

In relation to the use of comparators in controls, commentators have raised thethe question of standard of care to be provided to a control group. Theyemphasize that standard of care refers to more than the comparator drug orother intervention, andthat research subjects in the poorer countries do notusually enjoy the same standard of all-round care enjoyed by subjects in richercountries. This issue is not addressed specifically in the Guidelines.

In one respect the Guidelines depart from the terminology of the Declaration ofHelsinki.

‘Best current intervention’ is the term most commonly used to describethe active comparator that is ethically preferred in controlled clinical trials. Formany indications, however, there is more than one established

‘current’intervention and expert clinicians do not agree on which is superior. In othercircumstances in which there are several established ‘current’ interventions,some expert clinicians recognize one as superior to the rest; some commonlyprescribe another because the superior intervention may be locally unavailable,for example, or prohibitively expensive or unsuited to the capability of particularpatients to adhere to a complex and rigorous regimen. ‘Established effectiveintervention’ is the term used in Guideline 11 to refer to all such interventions,including the best and the various alternatives to the best. In some cases anethical review committee may determine that it is ethically acceptable to use anestablished effective intervention as a comparator, even in cases where such anintervention is not considered the best current intervention.

The mere formulation of ethical guidelines for biomedical research involvinghuman subjects will hardly resolve all the moral doubts that can arise inassociation with much research, but the Guidelines can at least draw theattention of sponsors, investigators and ethical review committees to the need toconsider carefully the ethical implications of research protocols and the conductof research, and thus conduce to high scientific and ethical standards ofbiomedical research.

INTERNATIONAL INSTRUMENTS AND GUIDELINES

The first international instrument on the ethics of medical research, theNuremberg Code, was promulgated in 1947 as a consequence of the trial ofphysicians (the Doctors’ Trial) who had conducted atrocious experiments onunconsenting prisoners and detainees during the second world war. The Code,designed to protect the integrity of the research subject, set out conditions for theethical conduct of research involving human subjects, emphasizing theirvoluntary consent to research.

The Universal Declaration of Human Rights was adopted by the GeneralAssembly of the United Nations in 1948. To give the Declaration legal as well asmoral force, the General Assembly adopted in 1966 the International Covenanton Civil and Political Rights. Article 7 of the Covenant states "No

one shall besubjected to torture or to cruel, inhuman or degrading treatment or punishment.In particular, no one shall be subjected without his free consent to medical orscientific experimentation".It is through this statement that society expresses thefundamental human value that is held to govern all research involving humansubjects–

the protection of the rights and welfare of all human subjects ofscientific experimentation.

The Declaration of Helsinki, issued by the World Medical Association in 1964, isthe fundamental document in the field of ethics in biomedical research and hasinfluenced the formulation of international, regional and national legislation andcodes of conduct. The Declaration, amended several times, most recently in2000 (Appendix 2), is a comprehensive international statement of the ethics ofresearch involving human subjects. It sets out ethical guidelines for physiciansengaged in both clinical and nonclinical biomedical research.

Since the publication of the CIOMS 1993 Guidelines, several internationalorganizations have issued

ethical guidance

on clinical trials. This has included,from the World

Health Organization, in 1995,Guidelines

for Good ClinicalPractice for Trials on Pharmaceutical Products; and from the InternationalConference on Harmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH),

in 1996,Guideline on Good ClinicalPractice, designed to ensure that data generated from clinical trials are mutuallyacceptable to regulatory authorities in the European Union, Japan and the UnitedStates of America. The Joint United Nations Programme on HIV/AIDSpublishedin 2000 the UNAIDS Guidance DocumentEthical Considerations in HIVPreventive Vaccine Research.

In 2001 the Council of Ministers of the European Union adopted a Directive onclinical trials, which will be binding in law in the countries of the Union from 2004.The Council of Europe, with more than 40 member States, is developing aProtocol on Biomedical Research, which will be an additional protocol to theCouncil’s 1997 Convention on Human Rights and Biomedicine.

Not specifically concerned with biomedical research involving human subjectsbut clearly pertinent, as noted above, are international human rights instruments.These are mainly the Universal Declaration of Human Rights, which, particularlyin its science provisions, was highly influencedby the Nuremberg Code; theInternational Covenant on Civil and Political Rights; and the InternationalCovenant on Economic, Social and Cultural Rights. Since the Nurembergexperience, human rights law has expanded to include

the protection of women(Convention on the Elimination of All Forms of Discrimination Against Women)and children (Convention on the Rights of the Child). These and other suchinternational instruments endorse in terms of human rights the general ethicalprinciples that underlie the CIOMS International Ethical Guidelines.

GENERAL ETHICAL PRINCIPLES

All research involving human subjects should be conducted in accordance withthree basic ethical principles, namely respect for persons, beneficence andjustice. It is generally agreed that

these principles, which in the abstract haveequal moral force, guide the conscientious preparation of proposals for scientificstudies. In varying circumstances they may be expressed differently and givendifferent moral weight, and their application may

lead to different decisions orcourses of action. The present guidelines are directed at the application of theseprinciples to research involving human subjects.

Respect for personsincorporates at least two fundamental ethicalconsiderations, namely:

a) respect for autonomy, which requires that those who are capable ofdeliberation about their personal choices should be treated with respect fortheir capacity for self-determination; and

b) protection of persons with impaired or diminished autonomy,which requires that those who are dependent or vulnerable beafforded security against harm or abuse.

Beneficence

refers to the ethical obligation to maximize benefits and to minimizeharms. This principle gives rise to norms requiring that the risks of research bereasonable in the light of the expected benefits, that the research design besound, and that the investigators be competent both to conduct the research andto safeguard the welfare of the research subjects. Beneficence further proscribesthe deliberate infliction of harm on persons; this aspect of beneficence issometimes expressed as a separate principle,nonmaleficence

(do no harm).

Justice

refers

to the ethical obligation to treat each person in accordance withwhat is morally right and proper, to give each person what is due to him or her. Inthe ethics of research involving human subjects the principle refers primarily todistributive justice,which requires the equitable distribution of both the burdensand the benefits of participation in research. Differences in distribution of burdensand benefits are justifiable only if they are based on morally relevant distinctionsbetween persons; one such distinction is vulnerability. "Vulnerability" refers to asubstantial incapacity to protect one's

own interests owing to such impedimentsas lack of capability to give informed consent, lack of alternative means of

obtaining medical care or other expensive necessities, or being a junior orsubordinate member of a hierarchical group. Accordingly, special provision mustbe made for the protection of

the rights and welfare of

vulnerable persons.

Sponsors of research or investigators cannot, in general, be held accountable forunjust conditions where the research is conducted, but they must refrain frompractices that are likely to worsen unjust conditions or contribute to newinequities. Neither should they take advantage of the relative inability of low-resource countries or vulnerable populations to protect their own interests, byconducting research inexpensively and avoiding complex regulatory systems ofindustrialized countries in order to develop products for the lucrative markets ofthose countries.

In general, the research project should leave low-resource countries orcommunities better off than previously or, at least, no worse off. It should beresponsive to their health needs and priorities in that any product developed ismade reasonably available to them, and as far as possible leave the populationin a better position to obtain effective health care and protect its own health.

Justice requires also that the research be responsive to the health conditions orneeds of vulnerable subjects. The subjects selected should be the leastvulnerable necessary to accomplish the purposes of the research. Risk tovulnerable subjects is most easily justified when it arises from interventions orprocedures that hold out for them the prospect of direct health-related benefit.Risk that does not hold out such prospect must be justified by the anticipatedbenefitto the population of which the individual research subject isrepresentative.

PREAMBLE

The term "research" refers to a class of activity designed to develop or contributeto generalizable knowledge. Generalizable knowledge consists of theories,principles or relationships, or the accumulation of information on which they arebased, that can be corroborated by accepted scientific methods of observationand inference. In the present context "research" includes both medical andbehavioural studies pertaining to human health. Usually "research" is modified bythe adjective "biomedical" to indicate its relation to

health.

Progress in medical care and disease prevention depends upon anunderstanding of physiological and pathological processes or epidemiological

findings, and requires at some time research involving human subjects. Thecollection, analysis and interpretation of information obtained from researchinvolving human beings contribute significantly to the improvement of humanhealth.

Research involving

human subjects includes:

-

studies of a physiological, biochemical or pathologicalprocess, or of the response to a specific intervention–

whether physical, chemical or psychological–

in healthysubjects or patients;

-

controlled trials of diagnostic,preventive ortherapeutic measures in larger groups of persons,designed to demonstrate a specific generalizableresponse to these measures against a background ofindividual biological variation;

-

studies designed to determine the consequences forindividuals and communities of specific preventive ortherapeutic measures; and

Research involving human subjects may employ either observation or physical,chemical or psychological intervention; it may also either generate records ormake use of existing records containing biomedical or other information aboutindividuals who may or may not be identifiable from the records or information.The use of such recordsand the protection of the confidentiality of data obtainedfrom those records are discussed inInternational Guidelines for Ethical Reviewof Epidemiological Studies (CIOMS, 1991).

The research may be concerned with the social environment, manipulatingenvironmental factors in a way that could affect incidentally-exposed individuals.It is defined in broad terms in order to embrace field studies of pathogenicorganisms and toxic chemicals under investigation for health-related purposes.

Biomedical researchwith human subjects is to be distinguished from the practiceof medicine, public health and other forms of health care, which is designed tocontribute directly to the health of individuals or communities. Prospectivesubjects may find it confusing when research and practice are to be conductedsimultaneously, as when research is designed to obtain new information aboutthe efficacy of a drug or other therapeutic, diagnostic or preventive modality.

As stated in Paragraph 32 of the Declaration of Helsinki, "In the treatment of apatient, where proven prophylactic, diagnostic and therapeutic methods do notexist or have been ineffective, the physician, with informed consent from thepatient, must be free to use unproven or new prophylactic, diagnostic andtherapeutic measures, if in the physician's judgement it offers hope of saving life,re-establishing health or alleviating suffering. Where possible, these measuresshould be made the object of research, designed to evaluate their safety andefficacy. In all cases, new information should be recorded and, whereappropriate, published. The other

relevant guidelines of this Declaration shouldbe followed."

Professionals whose roles combine investigation and treatment have a specialobligation to protect the rights

and welfare of the patient-subjects. An investigatorwho agrees to act as physician-investigator undertakes some or all of the legaland ethical responsibilities of the subject's primary-care physician. In such acase, if the subject withdraws from the research owing to complications related tothe research or in the exercise of the right to withdraw without loss of benefit, thephysician has an obligation to continue to provide medical care, or to see that thesubject receives the necessary care in the health-care system, or to offerassistance in finding another physician.

Research with human subjects should be carried out only by, or strictlysupervised by, suitably qualified and experienced investigators and inaccordance with a protocol that clearly states: the aim of the research; thereasons for proposing that it involve human subjects; the nature and degree ofany known risks to the subjects; the sources from which it is proposed to recruitsubjects; and the means proposed for ensuring that subjects'

consent will beadequately informed and voluntary. The protocol should be scientifically andethically appraised by one or more suitably constituted review bodies,independent of the investigators.

New vaccines and medicinal drugs, before being approved for general use, mustbe tested on human subjects in clinical trials; such trials constitute a substantialpart of all research involving human subjects.

The ethical justification of biomedical research involving human subjects is theprospect of discovering new ways of benefiting people's health. Such researchcan be ethically justifiable only if it is carried out in ways that respectand protect,and are fair to, the subjects of that research and are morally acceptable withinthe communities in which the research is carried out. Moreover, becausescientifically invalid research is unethical in that it exposes research subjects torisks

without possible benefit, investigators and sponsors must ensure thatproposed studies involving human subjects conform to generally acceptedscientific principles and are based on adequate knowledge of the pertinentscientific literature.

Commentary onGuideline 1

Among the essential features of ethically justified research involving humansubjects,including research with

identifiable

human tissue or data,

are that theresearch offers a means of developing information not otherwise obtainable, thatthedesign of the research is scientifically sound,

and that the investigators andother research personnel are competent. The methods to be used should beappropriate to the objectives of the research and the field of study. Investigatorsand sponsors must also ensure that all who participate in the conduct of theresearch are qualified by virtue of their education and experience to performcompetently in their roles. These considerations should be adequately reflectedin the research protocol submitted for review and clearance to scientific andethical review committees (Appendix I).

Scientific review is discussed further in the Commentaries to Guidelines 2 and 3:Ethical review committees

andEthical review of externally sponsored research.Other ethical aspects of research are discussed in the remaining guidelines andtheir commentaries.The protocol designed for submission for review andclearance to scientific and ethical review committees should include, whenrelevant, the items specified in Appendix I,

and should be carefully followed inconducting the research.

Guideline 2: Ethical review committees

All proposals to conduct research involving human subjects must be submittedfor review of their scientific merit and ethical acceptability to one or morescientific review and ethical review committees. The review committees

must beindependent of the research team, and any direct financial or other materialbenefit they may derive from the research should not be contingent on theoutcome of their review. The investigator must obtain their approval or clearancebefore undertaking the research. The ethical review committee should conductfurther reviews as necessary in the course of the research, including monitoringof the progress of the study.

Commentary on

Guideline 2

Ethical review committees may function at the institutional, local, regional, ornational level, and in some cases at the international level.The regulatory orother governmental authorities concerned should promote uniform standardsacross committees within a country, and, under all systems, sponsors ofresearch and institutions in which the investigators

are employed

should allocatesufficient resources to the review process.

Ethical review committees mayreceive money for the activity of reviewing protocols, but under no circumstancesmay payment be offered or accepted for a review committee`s approval orclearance of a protocol.

Scientific review.

According to the Declaration of Helsinki (Paragraph

11),medical research involving humans must conform to generally accepted scientificprinciples, and be based on a thorough knowledge of the scientific literature,other relevant

sources of information, and adequate laboratory and, whereindicated, animal experimentation. Scientific review must consider, inter alia, thestudy design, including the provisions for avoiding or minimizing risk and formonitoring safety. Committees competent to review and approve scientificaspects of research proposals must be multidisciplinary.

Ethical review.The ethical review committee is responsible for safeguarding therights, safety, and well-being of the research subjects. Scientific review andethical review cannot be separated: scientifically unsound research involvinghumans as subjects is ipso facto unethical in that it may expose them to risk orinconvenience to no purpose; even if there is no risk of injury, wasting of

subjects` and researchers`

time in unproductive activities represents loss of avaluable resource. Normally, therefore, an ethical review committee considersboth the scientific and the ethical aspects of proposed research. It must eithercarry out a proper scientific review or verify that a competent expert body hasdetermined that the research is scientifically sound. Also, it considers provisionsfor monitoring of data and safety.

If the

ethical review committee finds a research proposal scientifically sound, orverifies that a competent expert body has found it so, it should then considerwhether any known or possible risks to the subjectsare justified by the expectedbenefits, direct or indirect, and whether the proposed research methods willminimize harm and maximize benefit. (See Guideline 8:

Benefits and risks ofstudy participation.)If the proposal is sound and the balance of risks toanticipated benefits is reasonable, the committee should then determine

whetherthe procedures proposed for obtaining informed consent are satisfactory andthose proposed for the selection of subjects are equitable.

Ethical review of emergency compassionate use of an investigational therapy.Insome countries, drug regulatory authorities require that the so-calledcompassionate or humanitarian use of an investigational treatment be reviewedby an ethical review committee as though it were research. Exceptionally, aphysician may undertake the compassionate use of an investigational therapybefore obtaining the approval or clearance of an ethical review committee,provided three criteria are met:a patient needs emergency treatment, there issome evidence of possible effectiveness of the

investigational treatment, andthere is no other treatment available that is known to be equally effective orsuperior. Informed consent should be obtained according to the legalrequirements and cultural standards of the community in which the intervention iscarried out. Within one week the physician must report to the ethical reviewcommittee the details of the case and the action taken, and an independenthealth-care professional must confirm in writing to the ethical review committeethe treating physician's judgment that the use of the investigational interventionwas justified according to the three specified criteria. (See also Guideline 13Commentary section:Other vulnerable groups.)

National (centralized) or local review.Ethical review committees may be createdunder the aegis of national or local health administrations, national (orcentralized)

medical research councils or other nationally representative bodies.In a highly centralized administration a national, or centralized,

review committeemay be constituted for both the scientific and the ethical review of researchprotocols. In countries where medical research is not centrally administered,ethical review is more effectively and conveniently undertaken at alocal orregional level. The authority of a local ethical review committee may be confinedto a single

institution or may extend to all institutions in which biomedicalresearch is carried out within a defined geographical area. The basicresponsibilitiesof ethical review committees are:



to determine that all proposed interventions, particularly the administration ofdrugs and vaccines or the use of medical devices or procedures underdevelopment, are acceptably safe to be undertaken in humans or to verify

thatanother competent expert body has done so;



to determine that the proposed research is scientifically sound or to verify thatanother competent expert body has done so;



to ensure that all other ethical concerns arising from a protocol are satisfactorilyresolved both in principle and in practice;



to consider the qualifications of the investigators, including education in the

principles

of research practice, and the conditions of the research site with a viewto ensuring the safe conduct of the trial; and



to keep records of decisions and to take measures to follow up on the conduct ofongoing research projects.

o

Committee membership.National or local ethical review committees should beso composed as to be able to provide complete and adequate reviewof theresearch proposals

submitted to them. It is generally presumed that theirmembership should include physicians, scientists and other professionals suchas nurses, lawyers, ethicists and clergy, as well as lay persons qualified torepresent the cultural and moral values of the community and to ensure that therights of the research subjects will be respected.

They should include both menand women. When uneducated or illiterate persons form the focus of a study theyshould also be considered for membership

or invited to be represented and havetheir views expressed.

A

number of members should be replaced

periodically with the aim of blendingthe advantages of experience with those of fresh perspectives.

A national or local ethical review committee responsible for reviewing andapproving proposals for externally sponsored research should have among itsmembers or consultants persons who are thoroughly familiar with the customsand traditions of the population or community concerned and sensitive to issuesof human dignity.

Committees that often review research proposals directed at specific diseases orimpairments, such as HIV/AIDS or paraplegia, should invite or hear the views ofindividuals or bodies representing

patients with such diseases or impairments.Similarly, for research involving such subjects as children, students, elderlypersons or employees, committees should invite or hear the views of theirrepresentatives or advocates.

To maintain the review committee’s independence from the investigators andsponsors

and to avoid conflict of interest, any member with a special orparticular, direct or indirect, interest in a proposal should not take part in itsassessment if that interest could subvert the member`s objective judgment.Members of ethicalreview committees should be held to the same standard ofdisclosure as scientific and medical research staff with regard to financial or otherinterests that could be construed as conflicts of interest. A practical way ofavoiding such conflict of interest

is for the committee to insist on a declaration ofpossible conflict of interest by any of its members. A member who makes such adeclaration should then withdraw, if to do so is clearly the appropriate action totake, either

at the member`s own discretion or at the request of the othermembers. Before withdrawing, the member should be permitted to offercomments on the protocol or to respond to questions of other members.

Multi-centre research.Some research projects are designed to be conducted ina number of centres

in different communities or countries. Generally, to ensurethat the results will be valid, the study must be conducted in an identical way ateach centre. Such studies include clinical trials, research designed for theevaluation of healthservice programmes, and various kinds of epidemiologicalresearch. For such studies, local ethical or scientific review committees are notnormally

authorized to change doses of drugs, to change inclusion or exclusioncriteria, or to make other similar modifications.

They should be fully empoweredto prevent a study that they believe to be unethical. Moreover, changes that localreview committees believe are necessary to protect the research subjects shouldbe documented and reported to the research institution or sponsor responsiblefor the whole research programme for consideration and due action, to ensurethat all other subjects can be protected and that the research will be valid acrosssites.

To ensure the validity of multi-centre research, any changein the protocol shouldbe made at every collaborating centre or institution, or, failing this, explicit inter-centre comparability procedures must be introduced; changes made at some butnot all will defeat the purpose of multi-centre research. For some multi-centrestudies, scientific and ethical review may be facilitated by agreement amongcentres to accept the conclusions of a single review committee; its memberscould include a representative of the ethical review committee at each of thecentres at which the research is to be conducted, as well as individualscompetent to conduct scientific review. In other circumstances, a centralizedreview may be complemented by local review relating to the local participatinginvestigators and institutions. The central committee could review the study froma scientific and ethical standpoint, and the local committees could verify thepracticability of the study in their communities, including the infrastructures, thestate of training, and ethical considerations of local significance.

In a large multi-centre trial, individual investigators will not have authority to actindependently, with regard to data analysis or to preparation and publication ofmanuscripts, for instance. Such a trial usually has a

set of committees whichoperate under the direction of a steering committee and are responsible for suchfunctions and decisions.

The function of the ethical review committee in suchcases is to review the relevant

plans with the aim of avoiding abuses.

Sanctions.

Ethical review committees generally have no authority to imposesanctions on researchers who violate ethical standards in the conduct ofresearch involving humans. They may, however, withdraw ethical approval of aresearch project if judged necessary.

They should be required to monitor theimplementation of an approved protocol and its progression, and

to report toinstitutional or governmental authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that theyhave approved or in the conduct of the studies. Failure to submit a protocol to thecommittee should be considered a clear and serious violation of ethicalstandards.

Sanctions imposed by governmental, institutional, professional or other

authorities possessing disciplinary power should be employed as a last resort.Preferred methods of control include cultivation of an atmosphere of mutual trust,and education and support to promote in researchers and in sponsors thecapacity for ethical conduct of research.

Should sanctions become necessary, they should be directed at the non-compliant researchers or sponsors. They may include fines or suspension ofeligibility to receive research funding, to use investigational interventions, or topractise medicine. Unless there are persuasive reasons to do otherwise, editorsshould refuse

to publish the results of research conducted unethically, and retractany articles that are subsequently found to contain falsified or fabricated data orto have been based on unethical research. Drug regulatory authorities shouldconsider refusal to accept unethically obtained data submitted in support of anapplication for authorization to

market a product. Such sanctions, however, may

deprive of benefit not only the errant researcher or sponsor but also that segmentof

society intended to benefit from the research; such possible consequencesmerit careful consideration.

Potential conflicts of interest related to project support.Increasingly, biomedicalstudies receive funding from commercial firms. Such sponsors have goodreasons to support research methods that are ethically and scientificallyacceptable, but cases have arisen in which the conditions of funding could haveintroduced bias. It may happen that investigators have little

or no input into trialdesign, limited access to the raw data, or limited participation in datainterpretation, or that the results of a clinical trial may

not be published if they areunfavourable to the sponsor's product. This risk of bias may also be associatedwith other sources of support, such as government or foundations. As thepersons directly responsible for their work, investigators should not enter intoagreements that interfere unduly with their access to the data or their ability toanalyse the data independently, to prepare manuscripts, or to publish them.Investigators must also disclose potential or apparent conflicts of interest on theirpart to the ethical review committee or to other institutional committees designedto evaluate and manage such conflicts. Ethical review committees shouldtherefore ensure that these conditions are met. See alsoMulti-centre research,above.

Guideline 3: Ethical review of externally sponsored research

An external sponsoring organization and individual investigators

should submitthe research protocol for ethical and scientific review in the country of thesponsoring organization, and the ethical standards applied should be no lessstringent than they would be for research carried out in that country. The healthauthorities of the host country, as well as a national or local ethical reviewcommittee, should ensure that the proposed research is responsive to the healthneeds and priorities of the host country and meets the requisite ethicalstandards.

Commentary on Guideline 3

Definition.

The termexternally sponsored research

refers to research undertakenin a host country but sponsored, financed, and sometimes wholly or partly carriedout by an external international or national organization or pharmaceuticalcompany with the collaboration or agreement of the appropriate authorities,institutions and personnel of the host country.

Ethical and scientific review.Committees in both the country of the sponsor andthe host country have responsibility for conducting both scientific and ethicalreview, as well as the authority to withhold approval of research proposals thatfail to meet their scientific or ethical standards. As far as possible, there must beassurance that the review is independent and that there is

no conflict of interestthat might affect the judgement of

members of the review committees in relationto any aspect of the research. When the external sponsor is an internationalorganization, its review of the research protocol must be in accordance with itsown independent ethical-review procedures and standards.

Committees in the external sponsoring country or international organization

havea special responsibility to determine whether the scientific methods are soundand suitable to the aims of theresearch; whether the drugs, vaccines, devices orprocedures to be studied meet adequate standards of safety; whether there issound justification for conducting the research in the host country rather than inthe country of the external sponsor

or in another country; and whether theproposed research is in compliance with the ethical standards of the externalsponsoring country or international organization.

Committees in the host country have a special responsibility to determinewhether the objectives of

the research are responsive to the health needs andpriorities of that

country. The ability to judge the ethical acceptability of variousaspects of a research proposal requires a thorough understanding of acommunity's customs and traditions. The ethical

review committee in the hostcountry, therefore, must have as either members or consultants persons withsuch understanding; it will then be in a favourable position to determine the

acceptability of

the proposed means of obtaining informed consent and otherwiserespecting the rights of prospective subjects as well as of the means proposed toprotect the welfare of the research subjects.

Such persons should be able, forexample, to indicate suitable members of the community to serve asintermediaries between investigators and subjects, and to advise on whethermaterial benefits or inducements may be regarded as appropriate in the light of acommunity's gift-exchange and other customs and traditions.

When a sponsor or investigator in one country proposes tocarry out research inanother, the ethical review committees in the two countries may, by agreement,undertake to review different aspects of the research protocol.

In short, in respectof host countries either with developed capacity for independent ethical review orin which external sponsors and investigators are contributing substantially tosuch capacity, ethical review in the external, sponsoring country may be limitedto ensuring compliance with broadly stated ethical standards. The ethical reviewcommittee in the host country can be expected to have greater competence forreviewing the detailed plans for compliance, in view of its better understanding ofthe cultural and moral values of the population in which it is proposed to conductthe research;it is also likely to be in a better position to monitor compliance in thecourse of a study. However, in respect of research in host countries withinadequate capacity for independent ethical review, full review by the ethicalreview committee in the external sponsoring country or international agency isnecessary.

Guideline 4: Individual informed consent

For all biomedical research involving humans the investigator must obtain thevoluntary

informed consent of the prospective subject or, in the case of

anindividual who is not capable of giving informed consent, the permission of alegally authorized representative in accordance with applicable law. Waiver ofinformed consent is to be regarded as uncommon and exceptional, and must inall cases be approved by an ethical review committee.

Commentary on Guideline 4

General considerations.Informed consent is a decision to participate in research,taken

by a competent individual who has received the necessary information;who has adequately understood the information; and who, after considering theinformation, has arrived at a decision without having been subjected to coercion,undue influence or inducement, or intimidation.

Informed consent is based on the principle that competent individuals are entitledto choose freely whether to participate in research. Informed consent protects theindividual's freedom of choice and respects the individual's autonomy. As anadditional safeguard, it must always be complemented by independent ethicalreview of research proposals. This safeguard of independent review isparticularly important as

many individuals are limited in their capacity to giveadequate informed consent; they include young children, adults with severemental or behavioural disorders, and persons who are unfamiliar with medicalconcepts and technology (See Guidelines 13,

14, 15).

Process.Obtaining informed consent is a process that is begun when initialcontact is made with a prospective subject and continues throughout the courseof the study. By informing the prospective subjects,

by repetition and explanation,by answering their questions as they arise, and by ensuring that each individualunderstands each procedure, investigators

elicit their informed consent and in sodoing manifest respect for their dignity and autonomy. Each individual

must begiven as much time as is needed to reach a decision, including time forconsultation with family members or others. Adequate time and resources shouldbe set aside for informed-consent procedures.

Language.Informing the individual subject must not be simply a ritual recitationof the contents of a written document. Rather, the investigator must convey theinformation, whether orally or in writing, in language that suits the individual'slevel of understanding. The investigator

must bear in mind that the prospectivesubject`s ability to understand the information necessary to give informedconsent depends on that individual's maturity, intelligence, education and beliefsystem. It

depends also on the investigator's

ability and willingness tocommunicate with patience and sensitivity.

Comprehension.The investigator

must then ensure that the prospective subjecthas adequately understood the information. The investigator

should give eachone full opportunity to ask questions and should answer them honestly, promptlyand completely. In some instances the investigator

may administer an oral or awritten test or otherwise determine whether the information has been adequatelyunderstood.

Documentation of consent.

Consent may be indicated in a number of ways. Thesubject may imply consent by voluntary actions, express consent orally, or sign aconsent form. As a general rule, the subject should sign a consent form, or, in thecase of incompetence, a legal guardian or other duly authorized representativeshould do so. The ethical review committee may approve waiver of therequirement of a signed consent form if the research carries no more thanminimal risk–

that is, risk that is no more likely and not greater than that attachedto routine medical or psychological examination–

and if the procedures to beused are only those for which signed consent forms are not customarily requiredoutside the research context. Such waivers may also be approved whenexistence of a signed

consent form would be an unjustified threat to the subject'sconfidentiality. In some cases, particularly when the information is complicated, itis advisable to give subjects information sheets to retain; these may resembleconsent forms in all respectsexcept that subjects are not required to sign them.Their wording should be cleared by the ethical review committee. When consenthas been obtained orally, investigators are responsible for providingdocumentation or proof of consent.

Waiver of the consent

requirement.Investigators should never initiate researchinvolving human subjects without obtaining each subject's informed consent,unless they have received explicit approval to do so from an ethical reviewcommittee. However, when the research designinvolves no more than minimalrisk and a requirement of individual informed consent would make the conduct ofthe research impracticable

(for example, where the research involves onlyexcerpting data from subjects' records), the ethical review committee may waivesome or all of the elements of informed consent.

Renewing consent.

When material changes occur in the conditions or theprocedures of a study, and also periodically in long-term studies, the investigatorshould once again seek informed consent from

the subjects. For example, newinformation may have come to light, either from the study or from other sources,about the risks or benefits of products being tested or about alternatives to them.Subjects should be given such information promptly. In many

clinical trials,results are not disclosed to subjects and investigators until the study isconcluded. This is ethically acceptable if an ethical review

committee hasapproved their non-disclosure.

Cultural considerations. In some cultures an investigator

may enter a communityto conduct research or approach prospective subjects for their individual consentonly after obtaining permission from a community leader, a council of elders, oranother designated authority. Such customs must be respected.

In no case,however, may the permission of a community leader or other authority substitutefor individual informed consent. In some populations the use of a number of locallanguages may complicate the communication of information to potential subjectsand the ability of an investigator to ensure that they truly understand it. Manypeople in all cultures are unfamiliar with, or do not readily understand, scientificconcepts such as those of placebo or randomization. Sponsors and

investigators

should develop culturally appropriate ways to communicate information that isnecessary for adherence to the standard required in the informed consentprocess. Also, they should describe and justify in the research protocol theprocedure

they plan to use in communicating information to subjects. Forcollaborative research in developing countries the research project should, ifnecessary, include the provision of resources to ensure that informed consentcan indeed be obtained legitimately within different linguistic and cultural settings.

Consent to use for research purposes biological materials (including geneticmaterial) from subjects in clinical trials.Consent forms for the research protocolshould include a separate section for clinical-trial subjects who are requested toprovide their consent for the use of their biological specimens for research.Separate consent may be appropriate in some cases (e.g., if investigators arerequesting permission to conduct basic research which is not a necessary part ofthe clinical trial), but not in others (e.g., the clinical trial requires the use ofsubjects’ biological materials).

Use of medical records and biological specimens.Medical records and biologicalspecimens taken in the course of clinical care may be used for research withoutthe consent of the patients/subjects only if an ethical review committee hasdetermined that the research poses minimal risk, that the rights or interests of thepatients will not be violated, that their

privacy and confidentiality or anonymity areassured,

and that the research is designed to answer an important question and

would be impracticable

if the requirement for informed consent were to beimposed. Patients have a right to know that their records or specimens may beused for research.

Refusal or

reluctance of individuals to agree to participatewould not be evidence of impracticability sufficient to warrant waiving informedconsent. Records and specimens of individuals who have specifically rejectedsuch uses in the past may be used only in the case of public health emergencies.(See Guideline 18

Commentary,Confidentiality between physician and patient)

Secondary use of research records or biological specimens.Investigators maywant to use records or biological specimens that another investigator has used orcollected for use, in another institution in the same or another country.

Thisraises the issue of whether the records or specimens contain personal identifiers,or can be linked to such identifiers, and by whom. (See also

Guideline 18:

Safeguarding confidentiality) If informed consent or permission was required toauthorize the original collection or use

of such records or specimens for researchpurposes, secondary uses are generally constrained by the conditions specifiedin the original consent. Consequently, it is essential that the original consent

process anticipate, to the extent that this is feasible, any foreseeable plans forfuture

use of the records or specimens for research. Thus, in the original processof seeking informed consenta member of the research team should discuss with,and, when indicated, request the permission of,

prospective subjects as to: i)whether there will or could be any secondary use and, if so, whether suchsecondary use will be limited with regard to the type of study that may beperformed on such materials;

ii) the conditions under which investigators

will berequired to contact the research subjects for additional authorization forsecondary use; iii) the investigators'

plans, if any, to destroy or to strip

ofpersonal identifiers the records or specimens; and iv) the rights of subjects torequest destruction or anonymization of biological specimens or of records orparts of records that they might consider particularly sensitive, such asphotographs, videotapes or audiotapes.

Before requesting an individual's consent to participate in research, theinvestigator must provide the following information, in language or another formof communication that the individual can understand:

1.

that the individual is invited to participate in research, the reasons forconsidering the individual suitable for the research, and that participation isvoluntary;

2.

that the individual is free to refuse to participateand will be free to withdrawfrom the research at any time without penalty or loss of benefits to which heor she would otherwise be entitled;

3.

the purpose of the research, the procedures to be carried out by theinvestigator and the subject, and an explanation of how the research differsfrom routine medical care;

4.

for controlled trials,

an explanation of features of the research design (e.g.,randomization, double-blinding), and that the subject will not be told of theassigned treatment until the study has

been completed and the blind has beenbroken;

5.

the expected duration of the individual's participation (including numberand duration of visits to the research centre and the total time involved) andthe possibility of early termination of the trial or ofthe individual’sparticipation in it;

6.

whether money or other forms of material goods will be provided in returnfor the individual's participation and, if so, the kind and amount;

7.

that, after the completion of the study, subjects will be informed of thefindings of the research in general, and individual subjects will be informedof any finding that relates to their particular health status;

8.

that subjects have the right of access to their data on demand, even if thesedata lack immediate clinical utility (unless the ethical review committee hasapproved temporary or permanent non-disclosure of data, in which case thesubject should be informed of, and given, the reasons for such non-disclosure);

9.

any foreseeable risks, pain or discomfort, or inconvenience tothe individual(or others) associated with participation in the research, including risks tothe health or well-being of a subject’s spouse or partner;

10.

the direct benefits, if any, expected to result to subjects from participating inthe research

11.

the expected benefits of the research to the community or to society at large,or contributions to scientific knowledge;

12.

whether, when and how any products or interventions proven by theresearch to be safe and effective will be made available to subjects after theyhave completed their participation in the research, and whether they will beexpected to pay for them;

13.

any currently available alternative interventions or courses of treatment;

14.

the provisions that will be made to ensure respect for the privacy of subjectsand for the confidentiality of records in which subjects are identified;

15.

the limits, legal or other, to the investigators' ability to safeguardconfidentiality, and the possible consequences of breaches of confidentiality;

16.

policy with regard to the useof results of genetic tests and familial geneticinformation, and the precautions in place to prevent disclosure of the resultsof a subject's genetic tests

17.

to immediate family relatives or to others (e.g., insurance companies oremployers) without the consent of the subject;

18.

the sponsors of the research, the institutional affiliation of the investigators,and the nature and sources of funding for the research;

19.

the possible research uses, direct or secondary, of the subject`s medicalrecords and of biological specimens taken in the course of clinical care (Seealso Guidelines 4 and 18 Commentaries);

20.

whether it is planned that biological specimens collected in the research willbe destroyed at its conclusion, and, if not, details about their storage (where,how, for how long, and final disposition) and possible future use, and thatsubjects have the right to decide about such future use, to refuse storage, andto have the material destroyed (See Guideline 4 Commentary);

21.

whether commercial products may be developed from biological specimens,and whether the participant will receive monetary or other benefits from thedevelopment of such products;

22.

whether the investigator is serving only as an investigator or as bothinvestigator and the subject`s physician;

that treatment will be provided free of charge for specified types of research-related injury or for complications associated with the research, the natureand duration of such care, the name of the organization or individual thatwill provide the treatment, and whether there is any uncertainty regardingfunding of such treatment.

25.

in what way, and by what organization, the subject or the subject`s family ordependants will be compensated for disability or death resulting from suchinjury (or, when indicated, that there are no plans to provide suchcompensation);

26.

whether or not, in the country in which the prospective subject is invited toparticipate in research, theright to compensation is legally guaranteed;

27.

that an ethical review committee has approved or cleared the researchprotocol.

has adequateunderstanding of the relevant facts and of the consequences of participationand has had sufficient opportunity to consider whether to participate;



as a general rule, obtain from each prospective subject a signed form asevidence of informed consent–

investigators should justify any exceptions tothis general rule and obtain the approval

of the ethical review committee

(SeeGuideline 4 Commentary,Documentation of consent);



renew the informed consent of each subject if there are significant changes inthe conditions or procedures of the research or if new information becomesavailable that could affect the willingness of subjects to continue toparticipate; and,



renew the informed consent of each subject in long-term studies at pre-determined intervals, even if there are no changes

in the design or objectivesof the research.

Commentary on Guideline 6

The investigator is responsible for ensuring the adequacy of informed consentfrom each subject. The person obtaining informed consent should beknowledgeable about the research and capable of answering questions fromprospective subjects. Investigators in charge ofthe study must make themselvesavailable to answer questions at the request of subjects. Any restrictions on thesubject`s opportunity to ask questions and receive answers before or during theresearch undermines the validity of the informed consent.

In some types of research, potential subjects should receive counselling aboutrisks of acquiring a disease unless they take precautions. This is especially trueof HIV/AIDS vaccine research (UNAIDS Guidance Document

Withholding information and deception.Sometimes, to ensure the validity ofresearch, investigators withhold certain information in the consent process. Inbiomedical research, this typically takes the form of withholding

not told the purpose of tests performed to monitor their compliance with theprotocol, since if they knew their compliance was being monitored they mightmodify their behaviour and hence invalidate results. In most such cases, theprospective subjects are asked to consent to remain uninformed of the purposeof some procedures until the research is completed; after the conclusion of thestudy they are given the omitted information. In other cases, because a requestfor permission to withhold some information would jeopardize the validity of theresearch, subjects are not

told that some information has been withheld until theresearch has been completed.

Any such procedure must receive the explicitapproval of the ethical review committee.

Active deception of subjects is considerably more controversial than simplywithholding certain information. Lying to subjects

is a tactic not commonlyemployed in biomedical research. Social and behavioural scientists, however,sometimes deliberately misinform subjects to study their attitudes and behaviour.For example, scientists have pretended to be patients to study the behaviour ofhealth-care professionals and patients in their natural settings.

Some people maintain that active deception is never permissible. Others wouldpermit it in certain circumstances.

Deception is not permissible, however, incases in which the deception itself would disguise the possibility of

the subjectbeing exposed to more than minimal risk. When deception is deemedindispensable to the methods of a study the investigators must demonstrate to anethical review committee that no other research method would suffice; thatsignificant advancescould result from the research; and that nothing has beenwithheld that, if divulged, would cause a reasonable person to refuse toparticipate. The ethical review committee should determine the consequences forthe subject of being deceived, and

whether and how deceived subjects should beinformed of the deception upon completion of the research. Such informing,commonly called "debriefing", ordinarily entails explaining the reasons for thedeception. A subject who disapproves of having been deceived should

be offeredan opportunity to refuse to allow the investigator to use information thusobtained. Investigators and ethical review committees should be aware thatdeceiving research subjects may wrong them as well as harm them; subjectsmay resent not having been informed

when they learn that they have participatedin a study under false pretences.

In some studies there may be justification fordeceiving persons other than the subjects by either withholding or disguisingelements of information. Such tactics

are often proposed, for example, for studiesof the abuse of spouses or children. An ethical review committee must reviewand approve all proposals to deceive persons other than the subjects. Subjectsare entitled to prompt and honest answers to their questions; the ethical reviewcommittee must determine for each study whether others who are to be deceivedare similarly entitled.

Intimidation and undue influence.Intimidation in any form invalidates informedconsent. Prospective subjects who are patientsoften depend for medical careupon the physician/investigator, who consequently has a certain credibility intheir eyes, and whose influence over them may be considerable, particularly ifthe study protocol has a therapeutic component.They may fear, for example,that refusal to participate would damage the therapeutic relationship or result inthe withholding of health services. The physician/investigator must assure themthat their decision on whether to participate will not affect the therapeuticrelationship or other benefits to which they are entitled.

In this situation theethical review committee should consider whether a neutral third party shouldseek informed consent.

The prospective subject must not be exposed to undue influence. The borderlinebetween justifiable persuasion and undue influence is imprecise, however. Theresearcher should give no unjustifiable assurances about the benefits, risks orinconveniences of the research, for example, or induce a close relative or acommunity leader to influence a prospective subject's decision. (See alsoGuideline 4:

Individual informed consent.)

Risks.

Investigators should be completely objective in discussing the details ofthe experimental intervention, the pain and discomfort that it may entail, andknown risks and possible hazards.

In complex research projects it may be neitherfeasible nor

desirable

to inform prospective participants fully about every possiblerisk. They must, however, be informed of all risks that a ‘reasonable person’would

consider

material to making a decision about whether to participate,including risks to a spouse or partner associated with trials of, for example,psychotropic or genital-tract medicaments. (See also Guideline 8 Commentary,Risks to groups of persons.)

Exceptionto the requirement for informed consent in studies of emergencysituations in which the researcher anticipates that many subjects will be unable toconsent.

Research protocols are sometimes designed to address conditionsoccurring suddenly and rendering the patients/subjects incapable of givinginformed consent. Examples are head trauma, cardiopulmonary arrest andstroke. The investigation cannot be done with patients who can give informedconsent in time and there may not be time to locate a person havingthe authorityto give permission.

In such circumstances it is often necessary to proceed withthe research interventions very soon after the onset of the condition in order toevaluate an investigational treatment or develop the desired knowledge. As thisclass

of emergency exception can be anticipated, the researcher must secure thereview and approval of an ethical review committee

before initiating the study. Ifpossible, an attempt should be made to identify a population that is likely todevelop the condition to be studied. This can be done readily, for example, if thecondition is one that recurs periodically in individuals; examples include grandmal seizures and alcohol binges. In such cases, prospective subjects should becontacted while fully capab